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Anthraquinone compounds as anti cancer compounds

A compound, anthraquinone technology, applied in the field of N-oxides, can solve the problems of compound instability, inability to separate, difficult to separate, etc.

Inactive Publication Date: 2007-03-21
SOMANTA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] We attempted to synthesize the corresponding N-oxides of the compounds described by Pors et al. However, the oxidized compounds were unstable and difficult or impossible to isolate

Method used

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  • Anthraquinone compounds as anti cancer compounds
  • Anthraquinone compounds as anti cancer compounds
  • Anthraquinone compounds as anti cancer compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 and 2

[0146] Amination of leucoquinizarin and 5,8-dihydroxyquinizarin

[0147] 1-{[(2-dimethylamino) ethyl] amino}-4-{[2-(3-hydroxypiperidin-1-yl) ethyl] amino}-anthracene-9,10-dione ( HAQ22) and 1,4-bis-{[2-(3-hydroxypiperidin-1-yl)ethyl]-amino}-anthracene-9,10-dione (HAQ24)

[0148] Pass N 2 Next, a solution of N-N-dimethylethylenediamine (0.92 g, 10.42 mmol) and 1-(2-aminoethyl)-3-piperidin-3-ol (1.50 g, 10.42 mmol) in EtOH (5 mL) Simultaneously, a suspension of leucoquinizarin (0.63 g, 2.61 mmol) in EtOH (25 mL) was added. After stirring for 8 h at reflux temperature, the reaction mixture was stirred for an additional 14 h at room temperature. EtOH was removed in vacuo and the residue was added to ice-cold brine. The precipitated solid was isolated by filtration and lyophilized. Pass the dark blue solid through a short column of flash chromatography: first use CH 2 Cl 2 Remove non-polar by-products, then gradually increase the polarity to remove more by-products, and fina...

Embodiment 3

[0153] 1,4-bis-{[2-(3-hydroxymethylpiperidin-1-yl)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione (HAQ70)

[0154] Pass N 2[1-(2-Aminoethyl)-piperidin-3-yl]methanol (1.9 g, 12 mmol) in EtOH (2 mL) was added to stirring 5,8-dihydroxyquinizarine leuco (272 mg, 1 mmol) in EtOH (15 mL). After stirring at reflux temperature for 7 h, the reaction mixture was cooled to room temperature and stirred for an additional 16 h. EtOH was removed in vacuo and the residue was added to ice-cold brine. The precipitated solid was isolated by filtration and lyophilized. use CH 2 Cl 2 Then gradually increase the polarity to CH 2 Cl 2 / CH 3 OH (4:1), the dark blue solid was subjected to flash chromatography. then CH 2 Cl 2 / CH 3 OH / NH 3 (94:6:0.75) was used as eluent to subject the crude product to flash chromatography. The title compound (115.9 mg, 21%) was obtained as a dark blue solid. Melting point 180-183°C; δ H (250MHz; CDCl 3 ); 1.1-1.95(m, 12H, 2xOH and 10x ring-H), 2.25(m, ...

Embodiment 4

[0156] 1,4-bis-{[2-(3-hydroxymethylpiperidin-1-yl)ethyl]amino}-anthracene-9,10-dione (HAQ38)

[0157] Although not shown in Scheme 3, leucoquinizarin (0.23g, 0.95mmol), [1-(2-aminoethyl)-piperidin-3-yl]methanol (0.06g, 3.8mmol) and Ethanol (25mL), the same method as HAQ70. The title compound (0.15 g, 29%) was obtained as a dark blue solid. Melting point 112-114°C; δ H (250MHz; CDCl 3 ); 1.15(m, 2H, 2xCH 2 CHCH 2 OH), 1.5-1.75(m, 6H, 2xCH 2 CH 2 CH and 2xCH 2 CH 2 CH 2 ), 1.85(m, 2H, 2xCH 2 CH 2 CH), 2.3(m, 4H, 4xring-H), 2.5(s(b), 4H, 2xring-H, 2xOH), 2.65(t, 4H, J=5Hz, 2xHNCH 2 CH 2 N), 2.75(2xd, 2H, J=3Hz and 12Hz, 2x ring-H), 3.42(q, 4H, J=5Hz, 2xHNCH 2 CH 2 N), 3.55 (2xd, 2H, J=5Hz and 12Hz, 2xCHCH 2 OH), 3.7 (2xd, 2H, J=9Hz and 12Hz, 2xCHCH 2 OH), 7.1(s, 2H, C(2)H and C(3)H), 7.6(m, 2H, C(6)H and C(7)H), 8.3(m, 2H, C(5) )H, C(8)H) and 10.75(t, 2H, C(1)NH and C(4)NH); δ C (62.9MHz; CDCl 3 ); 24.08, 26.92, 37.90, 40.52, 54.43, 56.95, 57.75, 65.70, 109.89...

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Abstract

Anthraquinone compounds of the general formula (I) or a salt thereof (Formula I) in which R<1> to R<4> are each selected from the group consisting of H, C1-4 alkyl, X<1>, -NHR<0>N (R<5>)2 in which R<0> is a C1-12 alkanediyl and each R<5> is H or optionally substituted C1-4 alkyl, and a group of formula (II) in which at least one of R<6>,R<7> and R<8> is selected from X<2> , and X<2> substituted C1-4 alkyl and any others are H or C1-4 alkyl; R<9> is selected from H, C1-4 alkyl, X<2> and X<2> substituted C1-4 alkyl; m is 0 or 1; n is 1 or 2; X<1> is a halogen atom, a hydroxyl group, a C1-6 alkoxyl group, an aryloxy group or an acyloxy group; and X<2> is a halogen atom, a hydroxyl group, a C1-6 alkoxyl group, an aryloxy group or an acyloxy group; provided that at least one of R<1> to R<4> is a group of formula (II). The N-oxides are useful prodrugs which are selectively bioreduced in hypoxic tumours to the corresponding cyclic amine derivatives. The amine compounds are cytotoxic and may be used as alkylating agents having topoisomerase II inhibiting activities in cancer therapy.

Description

technical field [0001] The present invention relates to a series of substituted alkylaminoanthraquinones with nitrogen-containing heterocyclic substituents, and N-oxides of these compounds. The compound may be an alkylating agent having topoisomerase II inhibitory activity. The N-oxide is a prodrug. Background technique [0002] Resistance to antineoplastic drugs is a major cause of failure of cancer chemotherapy approaches, and many resistance mechanisms are known. For example, loss of DNA mismatch repair in in vitro models leads to resistance to many clinically important anticancer drugs, including cisplatin and doxorubicin, and it has also been shown that this loss is associated with hMLH1 gene activation. Related to hypermethylation of subregions. One approach to reverse this mechanism of drug resistance is to treat the cell line with a demethylating agent, thereby restoring the sensitivity of the cell line to conventional antineoplastic drugs. Treatment of human tum...

Claims

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Application Information

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IPC IPC(8): C07D207/06C07D211/22C07D211/46C07D207/12C07D207/08C07D211/18C07D211/38C07D207/10C07D207/46C07D211/94A61K31/445A61P35/00
Inventor L·H·帕特森K·波斯P·H·蒂斯戴尔－斯皮特尔
Owner SOMANTA LTD
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